The opening of cardiac sodium channels initiates action potentials in most cardiac cells. Despite this critical role in cardiac physiology, variatio in the underlying genes (notably SCN5A, which encodes the major sodium channel in heart) is surprisingly common, with a striking diversity of human phenotypes. Loss of sodium channel function predisposes to sudden death due to ventricular fibrillation: this is seen with sodium channel blockers in patients convalescing from acute myocardial infarction and with mutations that reduce cell surface channel expression. To date, major insights into channel function have come from studies of the relationship between rare genetic variants and unusual human phenotypes. In addition, more recent work has implicated common variants in genes underlying cardiac sodium channel function (including not only SCN5A but also SCN10A not previously implicated in cardiac function) as modulators of the normal electrocardiogram as well as of arrhythmia susceptibility. This resubmission proposal tests the general hypothesis that variation in channel function or expression generates an arrhythmia-prone substrate that becomes manifest in the presence of modulators such as drugs, myocardial ischemia, concomitant heart disease, or common genetic variation. Specific aim (1) will use pharmacological and genetic probes to dissect the role of SCN10A in cardiac sodium channel physiology. Specific aim (2) will examine the effects of common variants in SCN5A on sodium current in mice with wild-type and mutant human cardiac sodium channels. Variation in cardiac sodium channel physiology has been associated with increased propensity to sudden death, a continuing public health problem. The mechanisms are being attacked at the in vitro level, using heterologous expression, but the way in which these changes impact whole-heart function has not previously been addressed in detail and this is the major goal of the present experiments. Understanding mechanisms underlying arrhythmia susceptibility may lead to improved preventive treatments.